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(Hypertension. 1997;30:1112-1120.)
© 1997 American Heart Association, Inc.

Articles

Arginine Vasopressin Increases Nitric Oxide Synthesis in Cytokine-Stimulated Rat Cardiac Myocytes

Keiji Yamamoto; Uichi Ikeda; Koji Okada; Toshikazu Saito; Yasuhiro Kawahara; Masanori Okuda; Mitsuhiro Yokoyama; Kazuyuki Shimada

From the Departments of Cardiology (K.Y., U.I., K.S.) and Endocrinology and Metabolism (K.O., T.S.), Jichi Medical School, Minamikawachi, Tochigi, Japan, and the Department of Internal Medicine (Y.K., M.O., M.Y.), First Division, Kobe University School of Medicine, Hyogo, Japan.

Correspondence to Uichi Ikeda, MD, Department of Cardiology, Jichi Medical School, Minamikawachi, Tochigi 329-04, Japan. E-mail uikeda{at}jichi.ac.jp

Abstract We investigated the effects of arginine vasopressin (AVP) on nitric oxide (NO) synthase activity in cardiac myocytes by measuring the production of nitrite, a stable metabolite of NO, and the expression of inducible NO synthase (iNOS) mRNA and protein. Incubation of cultured neonatal rat cardiac myocytes for 24 hours with interleukin-1ß (IL-1ß) caused a significant increase in NO production. Both AVP and V_1a receptor agonist [Phe²,Ile³,Orn⁸]vasopressin augmented NO synthesis in IL-1ß–stimulated, but not in unstimulated myocytes, in a dose-dependent manner. The V_1a receptor antagonist [d(CH₂)₅¹,O-Me-Tyr²,Arg⁸]vasopressin completely inhibited the effect of AVP. The AVP-induced NO production by IL-1ß–stimulated cells was accompanied by increased iNOS mRNA and protein accumulation. AVP caused a significant increase in cytosolic free Ca²⁺ levels of cardiac myocytes, whereas it showed no effect on cytosolic cAMP levels. After protein kinase C activity was functionally depleted by treating cells with phorbol 12-myristate 13-acetate for 24 hours, AVP did not augment IL-1ß–induced NO production. The effect of AVP was also inhibited in the presence of the protein kinase C inhibitor calphostin C. The addition of AVP increased protein kinase C activity in cardiac myocytes, and its effect was significantly inhibited in the presence of calphostin C. These results support the hypothesis that the heart may be a target organ for AVP and that AVP modulates IL-1ß–induced iNOS expression in myocytes through the V_1a receptor, which is mediated at least partially via activation of protein kinase C.

Key Words: interleukins • endothelium-derived factors • calcium

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